Cortical and white matter anatomy relevant for the lateral and superior approaches to resect intraaxial lesions within the frontal lobe

Despite being associated with high-order neurocognitive functions, the frontal lobe plays an important role in core neurological functions, such as motor and language functions. The aim of this study was to present a neurosurgical perspective of the cortical and subcortical anatomy of the frontal lobe in terms of surgical treatment of intraaxial frontal lobe lesions. We also discuss the results of direct brain mapping when awake craniotomy is performed. Ten adult cerebral hemispheres were prepared for white matter dissection according to the Klingler technique. Intraaxial frontal lobe lesions are approached with a superior or lateral trajectory during awake conditions. The highly eloquent cortex within the frontal lobe is identified within the inferior frontal gyrus (IFG) and precentral gyrus. The trajectory of the approach is mainly related to the position of the lesion in relation to the arcuate fascicle/superior longitudinal fascicle complex and ventricular system. Knowledge of the cortical and subcortical anatomy and its function within the frontal lobe is essential for preoperative planning and predicting the risk of immediate and long-term postoperative deficits. This allows surgeons to properly set the extent of the resection and type of approach during preoperative planning.


Results
Measurements obtained during the study are summarized in Table 1 for the superior approach and in Table 2 for the lateral approach.
Superior approach (Figs. 1, 3 and 5; Table 1). The posterior anatomical border of the frontal lobe was defined by the central sulcus, whose main axis was projected to be approximately 70 degrees from the interhemispheric fissure (IHF) (Fig. 1D). This point can be identified approximately 5 cm posterior to the coronal suture along the interparietal suture. The width of the precentral gyrus at the level of the superor Rolandic point (SRP) was approximately 20 mm, which is two times wider than that at the base of the lobe at the inferior Rolandic point (IRP). The posterior part of the superior frontal gyrus is related to the presence of the SMA proper, which is approximately 20 mm and is anteriorly marked by the line perpendicular to the AC-PC line (anterior commissure -posterior commissure line) at the level of the AC. Aiming for the frontal lobectomy anterior to the SMA proper, the trajectory of the resection on the mesial surface must be at approximately 50 degrees to the superior margin of the hemisphere, and the genu of the corpus callosum can be reached at almost 90 mm. Following this trajectory, one would end the resection approximately 15 mm posterior to the most anterior part of the base of the frontal lobe. Changing the trajectory at that level of the genu of the corpus callosum perpendicular to the AC-PC line would extend resection for an additional 15 mm posteriorly, which would be almost half of the length of the base of the frontal lobe (Fig. 5A). On the lateral surface of the hemisphere, to achieve resection anterior to the precentral gyrus, one has to aim at an approximately 70-degree angle to the IHF, and the inferior frontal point was reached at approximately 75 mm. When assessing the bony anatomy, the end of resection from the lateral perspective is reached just posterior to the coronal suture and above the squamosal suture where the pars opercularis of the IFG is identified (Fig. 1C). At the level of the middle frontal gyrus, above the pars opercularis, the arcuate fasciculus/superior longitudinal fasciculus (AF/SLF) complex is identified at the subcortical including the precentral gyrus (blue), is located behind the coronal suture, and on the midline, the precentral gyrus is located approximately 4.5 cm behind bregma (red dot), while on the lateral surface, the precentral gyrus is located in proximity to the lateral sulcus 2.5 cm behind the stephanion (green dot). The coronal sutures are usually easily palpable through the skin, but in difficult cases, they can be identified approximately 13 cm behind the nasion along the midline (white dotted line) 13,27,35 . The inferior frontal gyrus (orange) is identified below the superior temporal line (red dotted line). The pars opercularis of the IFG is located behind the coronal suture, while the pars triangularis and orbitalis are located anteriorly. The middle (red) and superior frontal gyri (green) are located between the midline and the superior temporal line.
Lateral approach (Figs. 1, 4 and 5; Table 2). The horizontal ramus of the lateral sulcus corresponds to the inferior segment of the coronal suture, just above the squamosal suture. Posterior to these structures, the pars opercularis of the IFG is located anterior to the precentral gyrus (Fig. 1C). When performing frontal lobectomy from the lateral trajectory, the SMA proper/preSMA point is identified at approximately 85 mm along a line 80 degrees from the line parallel to the base of the frontal lobe and running parallel to the central sulcus and coronal suture starting at the level of the ascending ramus of the lateral sulcus. On the subcortical level, the dissection line in this direction runs tangential to the most rostral point of the AF/SLF complex and anterior to the anterior insular limiting sulcus. Anterior to the insula, the uncinate fascicle/inferior fronto-ocipital fascicle (UF/IFOF) complex was identified at a depth of approximately 25 mm from the cortical surface (Fig. 4E). Passing the UF/ IFOF complex, the midline is reached in the next 25 mm along the base of the frontal lobe, passing through the The lateral surface is localized anterior to the central sulcus (white dashed line), below the superior margin of the hemisphere and superior to the lateral sulcus (white square-dotted line) and free margin. The vertically oriented precentral gyrus (blue) containing the primary motor cortex is anterior to the central sulcus. The three horizontally oriented gyri of the frontal lobe (superior-green, middle-red and inferior-orange) separated by the superior and inferior sulci are located anterior to the precentral sulcus. (B) The inferior frontal gyrus is limited by the lateral sulcus inferiorly and inferior frontal sulcus superiorly and is divided into the pars orbitalis (light blue), pars triangularis (burgundy) and pars opercularis (pink) by the horizontal (white two-dash line) and ascending rami (white dot-dash line) of the lateral sulcus. (C) From the superior perspective, mainly the superior and middle gyri, which are separated by the superior frontal sulcus (black dashed line). (D) The basal surface of the frontal lobe is formed by a thin medially located gyrus rectus (purple), and a larger lateral part is formed by the four orbital gyri which are separated by the H-shaped orbital sulcus (black dotted line). The border between the lateral and medial parts is marked by the olfactory sulcus with the olfactory tract (black square dot line). (E) The mesial surface of the frontal lobe is formed by the paracentral lobule (yellow), superior frontal gyrus and cingulate gyrus, which are separated by the cingulate sulcus (white dotted line). The SMA proper is defined as the region anterior to the motor cortex. The anterior border is set by an imaginary line (red dotted line) perpendicular to the line connecting the anterior and posterior commissure, at the level of the anterior commissure. The anterior border of the pre-SMA is less defined, and it is marked by a line (blue dotted line) parallel to the previous and tangential to the most rostral part of the corpus callosum. f. The anterior surface of the lateral portion of the hemisphere is formed by the superior, middle and inferior frontal gyri, and the lateral sulcus is located laterally. www.nature.com/scientificreports/ olfactory groove 7 mm before midline. Above the AF/SLF complex, the posterior border of the dissection line is marked by the FAT (Fig. 4D).
Illustrative cases. Case 1 (Fig. 6). A 44-year-old right-handed man presented with an asymptomatic lesion characteristic of a LGG that was diagnosed with a full body MRI scan performed as a routine check-up on patient demand. The lesion was located within the dominant inferior frontal gyrus, being anterior to the AF/ SLF complex, and the FAT while being lateral to the IFOF. In the preoperative neuropsychological assessment, the patient presented with slight deficits in working memory and attention. The patient was operated in awake conditions in the lateral position with the head rotated to the right. Intraoperative electrical stimulation of the cortex posterior to the tumor elicited negative responses during picture naming tasks. These areas based on neuronavigation were related to the cortical terminations of the AF/SLF complex. In the postoperative period, patient presented without neurological deficits, while in the neuropsychological assessment increased preoperative deficits in working memory and attention were observed with additional subtle deficits in executive func- Case 2 (Fig. 7). A 31-year-old right-handed man presented with a history of seizures without neurological and cognitive deficits. MRI revealed a lesion characteristic of a LGG within the dominant superior frontal gyrus, being anterior to the SMA/FAT and medial to the AF/SLF complex. The patient was operated on in the semisitting position with the head in the neutral position, under awake conditions. Intraoperative electrical stimulation of the cortex posterior to the tumor elicited responses from the primary motor cortex. Stimulation of the white matter at the posterior border of resection elicited movement and naming arrest. These areas based on neuronavigation were related to the FAT. In the postoperative period, the patient presented with symptoms of transcortical motor aphasia, ideomotor apraxia and subtle deficits in attention which improved in the long-term follow-up. The final neuropathology was WHO grade II astrocytoma.

Discussion
The primary motor cortex. Permanent motor deficits related to frontal lobe surgery are related to injury to the cortical structures within the precentral gyrus-primary motor cortex. The traditional posterior bony landmark to avoid permanent motor deficits during frontal lobectomy is the coronal suture, which is localized approximately 13 cm from the nasion 13 . The coronal suture is located approximately 3.8 inferiorly and 5.3 cm superiorly anterior to the central sulcus and 2.3 inferiorly and 3.6 cm superiorly anterior to the precentral sulcus 14 . The main axis of the central sulcus is approximately 70 degrees anterior to the IHF, making the IRP closer than the SRP to the coronal suture, which is almost in the coronal plane. From a practical point of view during frontal lobectomy to avoid ventricular system and motor deficits the trajectory of the resection should be aiming from the coronal suture to the ridge of the lesser sphenoid wing which can easily be guided by the neuronavigation system (Case 3). Intraoperative stimulation of the precentral cortex and corticospinal tract subcorti-  There is ongoing debate about the usefulness of intraoperative mapping for the FAT/FST complex during awake conditions and the functional benefits of preservation in terms of neurooncological outcome due to mostly temporary deficits related to its resection 21,22 . The FAT connects the SMA complex and pars opercularis of the IFG, while the FST connects the SMA complex with the caudate nucleus 21,23 . This network was confirmed with in-vivo studies based on cortico-cortical evoked potentials (CCEPs) 24 . This technique also allows for intraoperative mapping and monitoring of language function under general anesthesia 25 . Intraoperative stimulation of FAT results in stuttering, speech arrest or problems with verb generation, while FST stimulation results in negative motor responses 21 . In the presented illustrative Case 2 intraoperative stimulation of the white matter at the posterior border of the resection resulted in arrest of speech and movement. Deficit was temporary and resolved in long term follow-up. The recovery mechanism in these patients is explained by crossed transcallosal fibers and recruitment of the contralateral, nondominant hemisphere 11,12,26 . This fiber system runs parallel to the precentral sulcus aiming for the pars opercularis of the IFG, mesial to the AF/SLF complex at the level of the middle frontal gyrus.
The pars opercularis. The pars opercularis is the most posterior compartment within the IFG, anterior to the precentral sulcus, behind the coronal suture and below the superior temporal line, and this structure measures approximately 7.5 mm according to present data 27 . Pars opercularis forms part of the ventrolateral premotor cortex, which should be preserved, especially on the dominant hemisphere, and limited brain plastic- where arrest of speech or movement (marker 2) and aphasia (marker 1) was observed. The posterior dissection plane was marked by arachnoid, while deeper on the subcortical level the stimulation was performed in the region where the AF/SLF complex was expected, and aphasia was observed. Anterior the resection was extended to the pars orbitalis, superior to the inferior frontal sulcus while at depth to the gyrus rectus and IFOF. DTI was reconstructed in DSI Studio (http:// dsi-studio. labso lver. org) 37 .
Scientific Reports | (2022) 12:21402 | https://doi.org/10.1038/s41598-022-25375-z www.nature.com/scientificreports/ ity within this region makes it often nonresectable 28 . Intraoperative stimulation of the dominant ventrolateral premotor cortex results in anarthria, while stimulation of the dorsolateral part results in anomia 29 . In terms of movement, intraoperative stimulation of the premotor cortex results in interruption of movement execution and alters patients' awareness of movement 30 . Within the premotor cortex where the middle frontal gyrus connects with the precentral sulcus lies the frontal eye field. The superior and inferior frontal points that mark the posterior ends of the middle frontal gyrus are located 27 and 51 mm from the IHF, respectively. Intraoperative stimulation of the frontal eye field results in saccadic eye movement, while cortical stimulation anterior to it may result in writing disabilities such as writing arrest or letter omissions 31 . This effect is related to Exner's area within the dominant hemisphere, which seems to be involved in the cognitive aspects of writing and reading 32 . The pars opercularis and anteriorly located pars triangularis constitute the so-called Broca's speech area, which stimulates arrest of speech and anomia and is approximately 28.3 mm in length in the widest dimension. The anterior 20.2 mm corresponds to the pars triangularis. Within this region, the frontal terminations of the AF/ SLF complex can be identified 20 . The AF/SLF complex represents the dorsal language pathway, which is the main tract related to language; when stimulated intraoperatively, it may result in speech production disorders of anomia and phonemic paraphasias and articulation disorders. The ventral language pathway is represented by the UF/IFOF complex, which is identified at the inferior-anterior border of the resection, mainly within the pars orbitalis of the frontal lobe 33 . Intraoperative brain stimulation during naming tasks can identify the UF/IFOF complex, as it produces semantic paraphasia in the dominant hemisphere and nonverbal semantic disturbances in the nondominant hemisphere. Resection of tumors located within the IFG is usually safe when performed anterior to the pars opercularis as presented in Case 1. The present results allowed systematization of the general superficial and white matter organization of the frontal lobe combining neuroanatomical basic science with neurosurgical perspective. Better understanding of the different anatomical layers of the frontal region, including craniometric points are crucial when planning surgery and strategies of intraoperative brain mapping what is essential in improving surgical and functional outcome. To the best of our knowledge, there is no such studies which combine all these aspects of the frontal lobe surgery with morphometrics measurements and anatomical dissections.
Limitations of the study. The physical parameters of the cadaveric brain tissue do not represent the intraoperative brain structure. The anatomical relationship between cortical and white matter structures in patients with tumors is disturbed by the tumor mass or edema. A better surgical perspective of the operation field would Medially, the falx cerebri (white rectangle) and contralateral frontal lobe (white dots) were identified. The patient was operated on in the semisitting position with the head in the neutral position. DTI was reconstructed in DSI Studio (http:// dsi-studio. labso lver. org) 37  www.nature.com/scientificreports/ be obtained with specimens containing preserved arterial and venous system vessels as well as preserved cranial structures. Additionally, when resections are based on function it cannot be related to the purely anatomical study.

Methods
Ten adult cerebral hemispheres with no intracranial pathology or description of neurological disease in their medical history were fixed with 4% formalin for at least 4 weeks. The dry brain, with arachnoid and vessels removed, was placed inside the freezer with at a temperature of -15 degrees Celsius for 2 weeks. For thawing and subsequent preservation, a 4% formalin solution at room temperature was used. The details of different modifications of the Klingler technique were described previously 36 . For dissections, the brain was placed in a position simulating the intraoperative scenario. For lesions in the SMA region and superior trajectory, the long axis of the brain was perpendicular to the floor, while for lesions in the frontal operculum and lateral trajectory, it was parallel to the floor (Fig. 1). The assessment of cortical anatomy was performed with the naked eye, while white matter dissection was performed in a stepwise manner with microscopic magnification (Fig. 2). The measurements included the distance between the constant anatomical cortical landmarks within the frontal lobe, white matter tracts and ventricular system. The localization of the tracts in relation to the main cortical landmarks was also taken into consideration. Measurements were made with an electric digital caliper, protractor and measuring tape. A digital camera (NikonD7200 with a Nikon DX 35 mm lens 1:1.8G) was used for image documentation. Color markers seen in the figures correspond to constant anatomical points and were placed for better anatomical orientation when the position of the brain or observation perspective was changed. Illustrative clinical cases present three different patients with LGG located within the frontal lobe (inferior frontal gyrus, superior frontal gyrus, whole frontal lobe) which may benefit from surgery with direct brain stimulation in terms of the extent of resection. The neuropsychological assessment of the patients was performed two days before the procedure, within a week and after a month. The diffusion images presented in the study were acquired on a GE SIGNA Architect scanner using a diffusion sequence. TE = 77.2 ms, and TR = 9541 ms. A DTI diffusion scheme was used, and a total of 63 diffusion sampling directions were acquired. The b-value was 1000.57 s/mm 2 . The in-plane resolution was 1.0156 mm. The slice thickness was 2 mm. The study was approved and the informed consent was waived by the Bioethics Committee of Medical University of Warsaw; the approval number is AKBE/126/2019. Informed consent for clinical data was obtained from all presented subjects. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Ethical approval. The study was approved by the Bioethics Committee of Medical University of Warsaw; the approval number is AKBE/126/2019. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.